Anti-inflammatory agent of benzoyl derivative

ABSTRACT

Anti-inflammatory agent comprises an active ingredient of benzoyl derivative having the formula ##STR1## WHEREIN R 1  represents hydrogen, hydroxy, C 1-8  alkyl or C 1-8  alkoxy, 
     R 2  represents hydrogen, halogen, hydroxy, vinyl, C 1-8  alkyl or C 1-8  alkoxy, 
     A represents carbonyl, methylene or a single bond, and 
     N is an integer of 1 to 4.

This is a division of application Ser. No. 755,069, filed Dec. 28, 1976.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to anti-inflammatory agent which comprises an active ingredient of non-carboxylic benzoyl derivative.

2. Description of the Prior Arts

It has been known to use Aspirine, Oxyphenyl butazone, Indomethacin, Phenyl butazone, Ketophenyl butazone, Azapropazone, Mephanamic acid, Ibufenac, Benzydamine, Aminophiline as non-steroid anti-inflammatory agent.

These medicines cause side-effects, gastroenteric disorder, headache, etc.

The inventors have studied various compound and have found that the specific benzoyl compounds which do not belong to classes of the known compounds in chemical formulae had excellent effects as anti-inflammatory agents and analgesics and also had thrombosis inhibiting effect.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel type anti-inflammatory agent and anti-thrombosis agent which does not cause side-effect.

Another object of the invention is to produce novel type anti-inflammatory agent.

The objects of the present invention have been attained by providing anti-inflammatory agent which comprises an active ingredient of non-carboxylic benzoyl derivative having the formula ##STR2## wherein R₁ represents hydrogen, halogen, hydroxy, C₁₋₈ alkyl or C₁₋₈ alkoxy,

R₂ represents hydrogen, halogen, hydroxy, vinyl, C₁₋₈ alkyl or C₁₋₈ alkoxy,

A represents carbonyl, methyleen or a single bond, and `n is an integer of 1 to 4.

It is preferable to be the active ingredient of benzoyl derivative having the formula ##STR3## wherein R'₁ repreents hydrogen, halogen or C₁₋₈ alkyl, R'₂ represents a substituent at ortho- or para-position which is hydrogen, C₁₋₈ alkyl or C₁₋₈ alkoxy,

A' represents carbonyl, methylene or a single bond, and

n' is an integer of 1 to 3.

I is especially preferable to be the active ingredient of ##STR4## wherein R"₁ represents hydrogen or halogen, and R"₂ represents hydrogen, C₃₋₈ alkyl or C₁₋₈ alkoxy, especially ##STR5##

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The benzoyl derivatives used in the invention do not cause side-effect of gastroenteric disorder and had low toxicity and neutral compounds as different from the conventional ones.

For example, the benzoyl derivatives having the formula ##STR6## wherein R₁, R₂, A and n are defined above; are produced by reacting a compound having the formula ##STR7## wherein R₁ and A are defined above and Hal represents a halogen atom with a compound having the formula ##STR8## wherein R₂ and n are defined above, in the presence of a catalyst and when A is --CH₂ --, A can be converted to --CO-- by reacting an oxidizing agent with the product.

The process for producing the benzoyl derivatives will be described in detail.

In the production of the compound I wherein A is a single bond or methylene group, the compound I is produced by reacting the compound II wherein A is a single bond or methylene group with the compound III in the presence of a catalyst.

Suitable catalysts include anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous stannic chloride and other catalysts for these reactions.

Suitable organic solvents such as carbon disulfide, dichloromethane, dichloroethane can be used in the reaction.

The reaction is usually completed at 25° to 75° C. with stirring for 3 to 20 hours.

After the reaction, the solvent is distilled off and water is added to the residue and the product is extracted with benzene and the solution was washed with a caustic alkali solution, and then with water and dried. The solvent is distilled off to obtain a crude object product (ketone). The purification of the product is carried out by a distillation under a reduced pressure or a recrystallization or the other conventional method.

In the production of the compound I wherein A is keto group, the reaction is carried out by using the compound I wherein A is methylene group in the presence of an oxidizing agent such as selenium oxide. In the reaction, suitable solvent such as dioxane, water, ethanol or a mixture thereof can be used. The reaction is usually completed at 110° to 150° C. for 5 to 90 hours.

After the reaction, the precipitate is filtered and the solvent is distilled off under a reduced pressure from the filtrate.

Water is added to the residue and the product is extracted with chloroform. The chloroform solution is dried and the solvent is distilled off to obtain the crude object compound (benzyl).

The purification can be carried out by the conventional method.

The anti-inflammatory agent of the invention can be applied by various manners such as oral dose, intravenous injection, intramuscular injection and embrocation.

The anti-inflammatory agent of the invention can be used in various forms such as tablet, capsule, injection, syrup, ointment and the other pharmaceutical compositions.

The active ingredients can be applied together with the other anti-inflammatory agent, analgesics, thrombus dissolving agent, thormbus formation inhibiting agent, antibiotics, etc.

The dose of the benzoyl derivative (I) is dependent upon the kinds of the object diseases and is usually 0.5 to 1000 mg/kg/day.

The benzoyl derivatives (I) had various pharmacological effects as shown in the following tablets. As the anti-inflammatory effect, 2-fluorobenzophenone, 4-n-butyl benzophenone, 4-n-butyl-2'-fluorobenzophenone, 4-n-amyl-2-fluorobenzophenone and 2'-fluoro-2,4,6-trimethyl benzophenone have especially high inhibition rate (ED₅₀).

The followings are typical examples of novel compounds of benzoyl derivatives of the invention:

2-Fluoro-4'-n-propyl-benzophenone

2-Fluoro-4'-n-butyl-benzophenone

2-Fluoro-4'-n-amyl-benzophenone

2-Fluoro-4'-methoxy-benzophenone

2-Fluoro-4'-sec.butyl-benzophenone

2-Fluoro-4'-sec.amyl-benzophenone

4-Fluoro-4'-n-butyl-benzophenone

2-Fluoro-2',4',6'-trimethyl-benzophenone

2-Chloro-4'-n-butyl-benzophenone

2-Bromo-4'-n-amyl-benzophenone

2-Bromo-4'-n-octyl-benzophenone

2-Fluoro-4'-iso-propyl-benzophenone

2-Iodo-4'-n-amyl-benzophenone

2-Methyl-4'-n-butyl-benzophenone.

EXAMPLE 1

A 2.8 g (0.02 mole) of benzoic acid chloride was dissolved in 30 ml of carbon disulfide and then, 4.0 g (0.03 mole) of anhydrous aluminum chloride was added to the solution. A 2.68 g (0.02 mole) of n-butyl benzene was further added to the mixture with stirring, and the reaction was carried out at room temperature for 18 hours. Carbon disulfide was distilled off from the reaction mixture and water was added and the reaction product was extracted with benzene. The benzene phase was separated and washed with 1N-NaOH and with water and was dried with anhydrous sodium sulfate.

The solvent was distilled off to obtain a pale yellow oily product. The oily product was distilled under a reduced pressure to obtain 4.6 g of 4-n-butyl benzophenone having a boiling point of 184° to 188° C./6 mmHg. (yield of 96.8%).

EXAMPLE 2

A 3.16 g (0.02 mole) of 2-fluoro benzoic acid chloride was dissolved in 30 ml of carbon disulfide and then, 4.0 g (0.03 mole) of anhydrous aluminum chloride was added to the solution.

A 2.68 g (0.02 mole) of n-butyl benzene was further added to the mixture with stirring, and the reaction was carried out at room temperature for 18 hours.

In accordance with the process of Example 1, the reaction mixture was treated to obtain 3.2 g of 4-n-butyl-2'-fluorobenzophenone having a boiling point of 180° to 190° C./5 mmHg. (yield of 62.5%).

EXAMPLE 3

A 21.4 g (0.16 mole) of n-butyl benzene and 25.0 g (0.162 mole) of phenyl acetic acid chloride were added to 100 ml of carbon disulfide, and 22.0 g (0.165 mole) of anhydrous aluminum chloride was further added to them with stirring and the reaction was carried out at room temperature for 15 hours.

In accordance with the process of Example 1, the reaction mixture was treated and the product was recrystallized from ethanol to obtain 39.0 g of 4-n-butyl-α-phenyl acetophenone having a melting point of 53° to 55° C. which had the formula ##STR9##

EXAMPLE 4

A 19.7 g (0.78 mole) of 4-n-butyl-α-phenyl acetophenone of Example 3 was dissolved in 200 ml of a mixture of dioxane 5; water 1, and 9.0 g (0.81 mole) of selenium dioxide was added to the solution and the mixture was heated under refluxing to react them for 90 hours. The resulting black precipitate was filtered off and the solvent was distilled off under a reduced pressure from the filtrate.

The residue was dissolved in chloroform and the solution was washed with water and was dried.

The solvent was distilled off under a reduced pressure and the resulting oily product was distilled under a reduced pressure to obtain 18.7 g of 4-n-butyl benzyl having a boiling point of 240° to 242° C./5 mmHg which had the formula ##STR10##

EXAMPLE 5

A 3.17 g (0.02 mole) of 2-fluorobenzoic acid chloride was dissolved in 30 ml of carbon bisulfide and then, 3.99 g (0.03 mole) of anhydrous aluminum chloride was added to the solution.

A 2.68 g (0.02 mole) of sec-butyl benzene was further added to the mixture with stirring and the reaction was carried out at room temperature for 18 hours. Carbon bisulfide was distilled off from the reaction mixture and water was added and the reaction product was extracted with benzene. The benzene phase was separated washed with 1N-NaOH and with water and was dried with anhydrous sodium sulfate. The solvent was distilled off to obtain a pale yellow oily product. The oily product was distilled under a reduced pressure to obtain 3.9 g of 4-sec-butyl-2'-fluorobenzophenone having a boiling point of 152° to 160° C./5 mmHg. (yield of 76.4%).

EXAMPLE 6

A 3.17 g (0.02 mole) of 2-fluorobenzoic acid chloride was dissolved in 30 ml of carbon disulfide and then, 3.99 g (0.03 mole) of anhydrous aluminum chloride was added to the solution. A 2.96 g (0.02 mole) of sec-amyl benzene was further added to the mixture with stirring and the reaction was carried out at room temperature for 18 hours.

In accordance with the process of Example 1, the reaction mixture was treated to obtain 4.0 g of 4-sec-amyl-2'-fluorobenzophenone having a boiling point of 150° to 157° C./4 mmHg. (yield of 74%).

The properties of the compounds produced in Examples 1 to 6 and the other compounds produced by the same manner are shown. The physical properties are shown in Table 1 and the pharmacological effects are shown in Table 2.

In the column for melting points and boiling points in Table 1, the symbol * means the melting point. In the column for IR in Table 1, the symbol * means ν_(max) ^(nujol) cm⁻¹.

In Table 2, the pharmacological effects and toxicity were measured by the following tests.

Anti-inflammatory effect

The edema inhibition rates (%) of the samples of the invention were measured in accordance with acute carragheenin edema method described in Nippon Yakurigaku Zatsushi Vol. 56, Page 575 in 1960.

The edema was induced by subcutaneous injection of 1% carragheenin suspension in saline to the hind paws of male rats weighting 150 to 180 g. Each sample was orally given at the dosage of 100 mg/kg just before the inoculation of carragheenin.

In Table 2, the values shown in brackets show the 50% inhibition rae ED₅₀ (mg/kg).

Analgesic effect

In accordance with the method described in Federation Proceedings Vol. 18, Page 412 in 1959, percentage diminition of times of painful stretchings (%) following the intraperitorineal injection of 0.7% acetic acid solution in male mice (weight of 20 to 25 g) were counted.

Each sample was orally administered in the dosage of 100 mg/kg before injection of acetic acid.

Blood platelet aggregation inhibiting effect

Male rabbits (Japan original white strain 3.3 to 3.6 kg) were anesthetized with Thiopental sodium and blood was sampled from the carotid artery.

In order to prevent coaggulation of the blood, 10% by volume of 3.8% sodium citrate aqueous solution was added to the blood.

The light transmittances were adjusted to 0% with PRP (supernatant platelet rich plasma separated by centrifugation at 1600 rpm from blood) and to 100% with PPP (supernatant platelet poor plasma separated by centrifugation at 3000 rpm from blood) by using the Blood platelet aggregometer (Model EEL-169, Electroserum Co. England). The platelet aggregation was measured in accordance with the test method described in Federation Preceedings Vol. 26, Page 115 in 1967, using collagen as an aggregation inducer.

The percent inhibition of platelet aggregation was given as the difference in the platelet aggregation rate % between the sample (concentration: 10⁻⁴ mole) and control (saline), with the rate of control adjusted to 100%.

Acute toxicity

Each sample was dissolved in olive oil or dispersed in 1% Tween 20 aqueous solution. The test was carried out by the oral dose in male mice having a weight of 22 to 25 g.

Ten animals were used at each of three or more dosage levels. General appearances and behaviors were observed for 7 days after treatment, and LD₅₀ was calculated on the basis of mice that succumbed within 72 hours using Van Der Warden method.

Inhibiting effect on thrombosis

The inhibiting effects of the samples of the invention on thrombosis were tested by the following test method.

SD type male rates (360 to 580 g) were anesthetized by the intraperitoneal injection of Thiopental sodium (67 mg/kg). In accordance with the technique described in Proceeding Society o Experimental Biological Medicine Vol. 139, Pages 548 to 552 in 1972 by Hermann, the by-pass was formed between the left juglar vein and the right carotid artery with a polyethylene tube.

A 0.5 ml of 50 μ/ml of the heparin physiological saline was added through the polyethylene tube before the first blood circulation. After the blood circulation for 15 minutes, the circulation was stopped in the middle of the tubing at artery side with a pinch cock.

Then, 0.2 ml of the heparin physiological saline was added to remove the blood coagulates on the tubing wall and another new polyethylene tubing filled with the heparin solution and containing a piece of new silk thread was attached between the venous and artery tubing ends.

The blood circulation was reestablished by opening the pinch cock. After 15 minutes, the wet weight of thrombus on the silk thread was similarly measured.

In the same manner, the third circulation was performed and wet weight of thrombus measured.

The amount of thrombus was given by the equation A. ##EQU1## Each sample was suspended in an aqueous solution of sodium carboxymethyl cellulose and the oral dose of the suspension (100 mg/kg) was performed at 5 hours before the first blood circulation.

The amount of thrombus after the oral dose of the sample was calculated in the same manner as that of control circulations.

The thrombosis inhibition rate was given by the equation B. ##EQU2##

The test results are shown in Table 2.

    ______________________________________                                         Composition 1:                                                                 ______________________________________                                         Active ingredient No. 8                                                                              100 g                                                    Fine powdery silica                                                            (Solider 101)         100 g                                                    Crystalline cellulose 645 g                                                    Corn starch           125 g                                                    Magnesium stearate     30 g                                                    ______________________________________                                    

The fine powdery silica was admixed with the same amount of the active ingredient No. 8, and the mixture was passed through a 32 mesh sieve.

The mixture was admixed with crystalline cellulose, corn starch and magnesium stearate and the components were uniformly mixed by passing through a 32 mesh sieve.

The mixture was treated by the tablet machine to form tablets having a diameter of 8 mm and a weight of 200 mg.

    ______________________________________                                         Composition 2:                                                                 ______________________________________                                         Active ingredient No. 3                                                                              125     g                                                Lactose               650     g                                                Crystalline cellulose 100     g                                                Corn starch           100     g                                                3% hydroxypropyl                                                               cellulose aqueous solution                                                                           500     ml                                               Magnesium stearate    10      g                                                ______________________________________                                    

The lactose, crystalline cellulose and corn starch were admixed with the active ingredient No. 3, and the mixture was passed through a 60 mesh sieve to uniformly mix the components. The mixture was charged in a kneader and 3% hydroxypropyl cellulose aqueous solution was added and the mixture was kneaded.

The mixture was granulated by passing through a 16 mesh sieve and was dried at 50° C. and then passed through a 16 mesh sieve to cause uniform particle sizes.

The granules were mixed with magnesium stearate and was treated by the tablet machine to form tablets having a diameter of 8 mm and a weight of 200 mg.

    ______________________________________                                         Composition 3:                                                                 ______________________________________                                         Active ingredient No. 119                                                                            100 g                                                    Fine powdery silica   100 g                                                    (Solider 101)                                                                  Crystalline cellulose 645 g                                                    Corn starch           125 g                                                    Magnesium stearate     30 g                                                    ______________________________________                                    

The fine powdery silica was admixed with the same amount of the active ingredient No. 119 and the mixture was passed through a 32 mesh sieve.

The mixture was admixed with crystalline cellulose, corn starch and magnesium stearate and the components were uniformly mixed by passing through a 32 mesh sieve.

The mixture was treated by the tablet machine to form tablets having a diameter of 8 mm and a weight of 200 mg.

    ______________________________________                                         Composition 4:                                                                 ______________________________________                                         Active ingredient No. 136                                                                            125     g                                                Lactose               650     g                                                Crystalline cellulose 100     g                                                Corn starch           100     g                                                3% hydroxypropyl cellulose                                                     aqueous solution      500     ml                                               Magnesium stearate    10      g                                                ______________________________________                                    

The active ingredient No. 136 was uniformly mixed with lactose, crystalline cellulose and corn starch by passing through a 60 mesh sieve.

The 3% hydroxypropyl cellulose aqueous solution was added to the mixture in a kneader and the mixture was granulated by passing through a 16 mesh sieve and was dried at 50° C. under air-flow. The dried granules were passed through a 16 mesh sieve to cause uniform particle sizes. The granules were mixed with magnesium stearate and was treated by the tablet machine to form tablets having a diameter of 8 mm and a weight of 200 mg.

                                      Table 1                                      __________________________________________________________________________                             Biling point                                           Active                  (° C./mmlig)                                    ingre-                  or       IR                                            dient                   melting  (CO)                                          No. R.sub.1                                                                              R.sub.2  A    point (° C.)                                                                     ν.sub.max.sup.nujol                        __________________________________________________________________________                                      cm.sup.-1                                     1   2-CH.sub.3                                                                           2,4-diCH.sub.3                                                                          single                                                                              155˜160/3                                                                         1660                                                             bond                                                        2   "     2,5-diCH.sub.3                                                                          "    148-152/3                                                                               1655                                          3   "     2,4,6-triCH.sub.3                                                                       "    111˜112*                                                                          1660*                                         4   4-n-C.sub.6 H.sub.13                                                                 2,4-diCH.sub.3                                                                          "    203˜5/4                                                                           1655                                          5   "     4-n-C.sub.4 H.sub.9                                                                     "    228/3    1650                                          6   "     4-n-C.sub.3 H.sub.7                                                                     "    213˜5/3                                                                           1650                                          7   2-F   "        "    160˜5/5                                                                           1660                                          8   "     4-n-C.sub.4 H.sub.9                                                                     "    180˜190/5                                                                         1660                                          9   "     4-n-C.sub.5 H.sub.11                                                                    "    190˜5/5                                                                           1660                                          10  "     2,4-diCH.sub.3                                                                          "    150˜5/5                                                                           1655                                          11  "     2,4,6-triCH.sub.3                                                                       "    155˜160/5                                                                         1660                                          12  H     4-OCH.sub.3                                                                             CO   180˜190/2                                                                         1660                                          13  "     2,4,6-triC.sub.2 H.sub.5                                                                single                                                                              176.5˜178/6.5                                                                     1665                                                             bond                                                        14  4-Cl  2,4,6-triCH.sub.3                                                                       "    65˜7*                                                                             1660*                                         15  H     2-F      "    190/29   1665                                          16  "     2,5-n-diC.sub.3 H.sub.7                                                                 "    172˜182/5                                                                         1665                                          17  4-CH.sub.3                                                                           2,5-n-diC.sub.4 H.sub.9                                                                 "    175˜191/2.5                                                                       1660                                          18  4-OCH.sub.3                                                                          4-n-C.sub.4 H.sub.9                                                                     "             1645                                          19  H     "        "    184˜188/6                                                                         1660                                          20  "     4-n-C.sub.3 H.sub.7                                                                     "    161˜167/3.5                                                                       1660                                          21  "     4-i-C.sub.3 H.sub.7                                                                     "    143˜4/2                                                                           1660                                          22  "     4-t-C.sub.4 H.sub.9                                                                     "    141˜144/1                                                                         1660                                          23  "     4-n-C.sub.5 H.sub.11                                                                    "    164˜167/2.5˜3                                                               1660                                          24  "     4-n-C.sub.6 H.sub.13                                                                    "    185˜190/3                                                                         1655                                          25  "     4-n-C.sub.7 H.sub.15                                                                    "    173˜175/2˜2.5                                                               1660                                          26  "     4-n-C.sub.8 H.sub.17                                                                    "    185˜190/3                                                                         1655                                          27  "     H        "    48˜49.5*                                                                          1660*                                         28  "     4-OCH.sub.3                                                                             "    58˜60*                                                                            1660                                          29  "     4-n-C.sub.4 H.sub.9                                                                     CO   240˜242/5                                                                         1660                                          30  "     2,4,6-triCH.sub.5                                                                       single                                                                              131˜133/1.5˜2                                                               1665                                                             bond                                                        31  "     2,3,4-triCH.sub.3                                                                       "    145.5˜148/2                                                                       1665                                          32  "     2,4,5-triCH.sub.3                                                                       "    152˜154/3                                                                         1665                                          33  4-CH.sub.3                                                                           4-C.sub.2 H.sub.5                                                                       "    46˜9*                                                                             1645*                                         34  "     4-n-C.sub.3 H.sub.7                                                                     "    160˜3/3                                                                           1650                                          35  "     4-n-C.sub.4 H.sub.9                                                                     "    160˜5/3                                                                           1655                                          36  "     4-n-C.sub.6 H.sub.13                                                                    "    190˜6/2                                                                           1650                                          37  H     2,4-diCH.sub.3                                                                          "    120˜122/1˜1.5                                                               1660                                          38  "     2,5-diCH.sub.3                                                                          "    132˜134.5/3                                                                       1665                                          39  "     4-n-C.sub.4 H.sub.9                                                                     CH.sub.2                                                                            53˜55*                                                                            1670*                                         40  2-CH.sub.3                                                                           "        single                                                                              157˜163/2                                                                         1665                                                             bond                                                        41  "     4-n-C.sub.5 H.sub.11                                                                    "    159˜169/1                                                                         1665                                          42  H     4-n-OC.sub.4 H.sub.9                                                                    "    27˜29*                                                                            1650*                                         43  4-n-C.sub.4 H.sub.9                                                                  4-n-C.sub.4 H.sub.9                                                                     "    205˜210/3.5                                                                       1650                                          44  2-Cl  4-n-C.sub.4 H.sub.9                                                                     "    200˜5/5                                                                           1660                                          45  4-OCH.sub.3                                                                          4-n-C.sub.5 H.sub.11                                                                    "             1645                                          46  4-n-C.sub.4 H.sub.9                                                                  4-F,2-CH.sub.3                                                                          "    140˜142/3                                                                         1650                                          47  H     H        CH.sub.2                                                                            55*      1670*                                         48  "     4-CH.sub.3                                                                              "    104˜ 106*                                                                         1670*                                         49  H     4-n-C.sub.3 H.sub.7                                                                     CH.sub.2                                                                            53-54*   1670*                                         50  "     4-n-C.sub.10 H.sub.21                                                                   "    50-52*   1670*                                         51  "     4-n-C.sub.11 H.sub.23                                                                   "    51-53*   1670*                                         52  "     4-n-C.sub.12 H.sub.25                                                                   "    55-58*   1670*                                         53  "     H        CO   95*      1660*                                         54  "     4-CH.sub.3                                                                              "    180/1    1660                                          55  "     4-C.sub.2 H.sub.5                                                                       "    170/1    1660                                          56  "     4-n-C.sub.6 H.sub.13                                                                    "    200-210/1                                                                               1660                                          57  "     4-OCH.sub.3                                                                             CH.sub.2                                                                            66-68*   1660*                                         58  "     4-n-OC.sub.3 H.sub.7                                                                    "    85-87*   1670*                                         59  "     4-n-OC.sub.5 H.sub.11                                                                   "    62-65*   1675*                                         60  4-Cl  4-OCH.sub.3                                                                             "    118-119* 1630*                                         61  "     4-n-OC.sub.4 H.sub.9                                                                    "    100-101* 1630*                                         62  "     4-n-OC.sub.6 H.sub.13                                                                   "    88-89*   1630*                                         63  "     4-n-C.sub.3 H.sub.7                                                                     single                                                                              77-78*   1640*                                                            bond                                                        64  "     4-n-C.sub.4 H.sub.9                                                                     "    62-53*   1640*                                         65  H     4-CH.sub.3                                                                              "    45-47*   1640*                                         66  "     4-C.sub.2 H.sub.5                                                                       "    133-134/2                                                                               1655                                          67  "     4-i-C.sub.4 H.sub.9                                                                     "    170-172/4                                                                               1655                                          68  "     4-n-C.sub.10 H.sub.21                                                                   "    205-210/2                                                                               1660                                          69  "     4-n-C.sub.12 H.sub.25                                                                   "    215-219/2                                                                               1660                                          70  "     4-n-C.sub.9 H.sub.19                                                                    "    187-194/25-3                                                                            1665                                          71  H     4-n-C.sub.11 H.sub.23                                                                   "    19914 209/2.5                                                                           1660                                          72  "     3,4-diCH.sub.3                                                                          "    139-144/1                                                                               1660                                          73  "     4-cycloC.sub.6 H.sub.13                                                                 "    170-182/1                                                                               1660                                          74  "     2,4-diOCH.sub.3                                                                         "    87-88*   1660*                                         75  "     2,5-diOCH.sub.3                                                                         "    50-52*   1660*                                         76  "     2,4,6-triOCH.sub.3                                                                      "    178-179* 1660*                                         77  "     2,5-di-n-C.sub.4 H.sub.9                                                                "    158-169/2                                                                               1660                                          78  "     2,3,5,6-tetraCH.sub.3                                                                   "    116-118* 1670*                                         79  "     2,3,4,6-tetraCH.sub.3                                                                   "    171-172/5.5                                                                             1670                                          80  "     2,5-diC.sub.2 H.sub.5                                                                   "    161-165/4                                                                               1665                                          81  "     4-OC.sub.2 H.sub.5                                                                      "    38-39*   1645*                                         82  "     4-CHCH.sub.2                                                                            "    oily     1660                                          83  4-CH.sub.3                                                                           4-CH.sub.3                                                                              "    91-93*   1645*                                         84  "     4-n-C.sub.5 H.sub.11                                                                    "    170-175/2                                                                               1655                                          85  "     4-n-C.sub.7 H.sub.15                                                                    "    195-203/3                                                                               1650                                          86  "     2,4,6-tri CH.sub.3                                                                      "    148-149/2.5                                                                             1665                                          87  3-CH.sub.3                                                                           4-n-C.sub.3 H.sub.7                                                                     "    162-165/4                                                                               1650                                          88  "     4-n-C.sub.4 H.sub.9                                                                     "    165-170/3                                                                               1650                                          89  "     4-n-C.sub.5 H.sub.11                                                                    "    175-180/3                                                                               1650                                          90  2-CH.sub.3                                                                           4-n-C.sub.3 H.sub.7                                                                     "    140-147/1.5                                                                             1665                                          91  "     2,3,5,6-tetraCH.sub.3                                                                   "    105-107* 1660*                                         92  4-OCH.sub.3                                                                          4-OCH.sub.3                                                                             "    141-142* 1640*                                         93  4-OCH.sub.3                                                                          4-n-C.sub.3 H.sub.7                                                                     "    oily     1645                                          94  4-n-OC.sub.4 H.sub.9                                                                 2,4,6-triCH.sub.3                                                                       "    190-194/3                                                                               1660                                          95  "     4-n-C.sub.4 H.sub.9                                                                     "    190-210/3                                                                               1650                                          96  4-n-C.sub.3 H.sub.7                                                                  2,4-diCH.sub.3                                                                          "    185/4    1655                                          97  "     2,4,6-triCH.sub.3                                                                       "    183-185/4                                                                               1650                                          98  "     4-n-C.sub.4 H.sub.9                                                                     "    207-210/3.5                                                                             1655                                          99  "     4-n-C.sub.5 H.sub.11                                                                    "    217-220/4                                                                               1650                                          100 4-n-C.sub.4 H.sub.9                                                                  4-n-C.sub.7 H.sub.15                                                                    "    oily     1650                                          101 "     4-n-C.sub.8 H.sub.17                                                                    "    "        1650                                          102 "     4-n-C.sub.9 H.sub.19                                                                    "    .spsb.1  1650                                          103 4-n-C.sub.6 H.sub.13                                                                 2,4,6-triCH.sub.3                                                                       "    205-210/4                                                                               1660                                          104 4-OH  4-n-C.sub.3 H.sub.7                                                                     "             1630                                          105 "     4-n-C.sub.5 H.sub.11                                                                    "             1630                                          106 4-C.sub.2 H.sub.5                                                                    4-C.sub.2 H.sub.5                                                                       "    47*      1650*                                         107 4-OCH.sub.3                                                                          4-C.sub.2 H.sub.5                                                                       "    41-43*   1640*                                         108 4-OH  2,4,6-triCH.sub.3                                                                       "             1630                                          109 H     4-OH     "    132-135* 1630*                                         110 4-n-C.sub.3 H.sub.7                                                                  4-n-C.sub.3 H.sub.7                                                                     "    65-67*   1650*                                         111 4-n-C.sub.5 H.sub.11                                                                 4-n-C.sub.5 H.sub.11                                                                    "    220-222/4                                                                               1650                                          112 4-n-C.sub.2 H.sub.5                                                                  4-n-C.sub.3 H.sub.7                                                                     "             1660                                          113 H                                                                                     ##STR11##                                                                              "    146-147* 1660*                                         114 4-F   4-F      "    102-105* 1640*                                         115 2-Cl  4-F      "    60-62*   1660*                                         116 2-F   4-OCH.sub.3                                                                             "    155-160/5                                                                               1660                                          117 "     4-i-C.sub.3 H.sub.7                                                                     "    142-152/5                                                                               1655                                          118 "     4-i-C.sub.4 H.sub.9                                                                     "    152-7/4  1660                                          119 "     4-s-C.sub.4 H.sub.9                                                                     "    155-160/5                                                                               1660                                          120 "     4-t-C.sub.4 H.sub.9                                                                     "    152-157/5                                                                               1660                                          121 "     4-s-C.sub.5 H.sub.11                                                                    "    150-7/4  1655                                          122 "     4-t-C.sub.5 H.sub.11                                                                    "    160-5/5  1665                                          123 3-F   4-n-C.sub.4 H.sub.9                                                                     "    182-7/5  1660                                          124 "     4-n-C.sub.5 H.sub.11                                                                    "    185-195/5                                                                               1655                                          125 "     2,4,6-triCH.sub.3                                                                       "    oily     1670                                          126 "     2,4-di-CH.sub.3                                                                         "    150-3/5  1660                                          127 4-F   4-n-C.sub.4 H.sub.9                                                                     "    39-40*   1645*                                         128 "     4-n-C.sub.5 H.sub.11                                                                    "    46-7*    1645*                                         129 "     4-n-C.sub.8 H.sub.17                                                                    "    32-3*    1645*                                         130 "     2,4-diCH.sub.3                                                                          "    149-152/5                                                                               1660                                          131 "     2,4,6-triCH.sub.3                                                                       "    150-2/5  1670                                          132 2-Cl  4-n-C.sub.3 H.sub.7                                                                     "    188-190/5                                                                               1660                                          133 "     4-n-C.sub.5 H.sub.11                                                                    "    200-4/5  1665                                          134 "     4-n-C.sub.8 H.sub.17                                                                    "    235-7/5  1665                                          135 "     2,4-diCH.sub.3                                                                          "    174-6/5  1660                                          136 4-Cl  4-OCH.sub.3                                                                             "    118-9*   1630.sup.N*                                   137 "     4-OC.sub.4 H.sub.9                                                                      "    100-1*   1630.sup.N*                                   138 "     4-OC.sub.6 H.sub.13                                                                     "    88-9*    1630.sup.N*                                   139 3-Cl  4-n-C.sub.3 H.sub.7                                                                     "    27-8*    1670*                                         140 "     4-n-C.sub.5 H.sub.11                                                                    "    355-7*   1660*                                         141 "     4-n-C.sub.8 H.sub.17                                                                    "    oily     1660                                          142 2-Br  4-n-C.sub.3 H.sub.7                                                                     "    39-40*   1670*                                         143 "     4-n-C.sub.4 H.sub.9                                                                     "    203-210/5                                                                               1660                                          144 "     4-n-C.sub.5 H.sub.11                                                                    "    210-215/5                                                                               1670                                          145 "     4-n-C.sub.8 H.sub.17                                                                    "    240-3/4  1665                                          146 "     2,4-diCH.sub.3                                                                          "    182-3/5  1660                                          147 "     2,4,6-triCH.sub.3                                                                       "    113-4*   1670*                                         148 3-Br  4-n-C.sub.8 H.sub.17                                                                    "    240-5/6  1650                                          149 "     2,4-diCH.sub.3                                                                          "    180-2/6  1650                                          150 4-Br  4-n-C.sub.3 H.sub.7                                                                     "    93-4*    1640*                                         151 "     4-n-C.sub.8 H.sub.17                                                                    "    53-4*    1640*                                         152 "     2,4-diCH.sub.3                                                                          "    180-5/6  1655                                          153 "     2,4,6-triCH.sub.3                                                                       "    70-1*    1660*                                         154 2-I   4-n-C.sub.3 H.sub.7                                                                     "    190-7/5  1660                                          155 "     4-n-C.sub.4 H.sub.9                                                                     "    202-9/4  1660                                          156 "     4-n-C.sub.5 H.sub.11                                                                    "    207-218/4                                                                               1660                                          157 "     4-n-C.sub.8 H.sub.17                                                                    "    215-220/4                                                                               1665                                          158 2-I   2,4-diCH.sub.3                                                                          "    192-7/5  1660                                          159 "     2,4,6-triCH.sub.3                                                                       "    97-8*    1665*                                         160 3-I   4-n-C.sub.4 H.sub.9                                                                     "    45-7*    1645*                                         161 "     4-n-C.sub.8 H.sub.17                                                                    "    215-20/4 1655                                          162 "     2,4-diCH.sub.3                                                                          "    74-5*    1655*                                         163 "     2,4,6-triCH.sub.3                                                                       "    85-6*    1660*                                         164 4-I   4-n-C.sub.8 H.sub.17                                                                    "    64-5*    1640*                                         165 "     2,4-diCH.sub.3                                                                          "    200-5/7  1655                                          166 "     2,4,6-triCH.sub.3                                                                       "    72-3*    1665*                                         __________________________________________________________________________

In Table, the following references are shown for columns.

                  Table 2                                                          ______________________________________                                         Anti-inf. =                                                                               edema inhibition rate (%)                                                      for anti-inflammatory effect;                                       Analgesic =                                                                               percentage diminition of times of painful                                      stretching (%) for analgesic;                                       Blood platelet                                                                 agg. inh. =                                                                               percentage inhibition of platelet aggregation                                  for blood platelet aggregation inhibiting                                      effect;                                                             Thrombosis                                                                     inh. =     thrombosis inhibition rate for                                                 inhibiting effect on thrombosis.                                    Active                    Blood Acute                                          ingre-                    platelet                                                                             toxicity                                                                              Thrombo-                                dient Anti-inf. Analgesic agg.  LD.sub.50                                                                             sis inh.                                No.   (%)       (%)       inh.  (mg/kg)                                                                               (%)                                     ______________________________________                                         1     36.2 (700)                                                                               10.2      21.7  1000   28.5                                    2     36.8      13.5      19.5  1000   30.3                                    3     40.0 (290)                                                                               11.3      17.3  1500   38.3                                    4     44.2      16.3      20.5  4000   15.9                                    5     46.3      12.1      15.3  5000   20.3                                    6     44.2      14.5      17.8  5000   15.9                                    7     55.6 (78) 15.0      23.0  1500   24.6                                    8     82.6 (38) 14.8      24.0  1500   38.0                                    9     74.6 (22) 15.3      14.6  3000   25.3                                    10    47.5 (90) 20.3      18.5  500    29.7                                    11    62.3 (22) 13.9      16.5  500    42.9                                    12    43.9      10.2      20.1  10000  18.3                                    13    38.9 (>400)                                                                              15.8      14.3  2000   20.5                                    14    37.3 (130)                                                                               19.2      18.1  500    23.3                                    15    61.4 (65) 18.5      23.2  4000   26.5                                    16    45.2 (140)                                                                               12.4      8.6   1500   21.5                                    17    36.3 (180)                                                                               10.3      17.3  2000   19.5                                    18    41.6      20.1      9.3   2000   24.2                                    19    63.4 (25) 30.1      18.6  2400   7.9                                     20    42.7      17.3      36.6  2000   4.1                                     21    37.3      16.1      8.6   2000   5.4                                     22    36.4      8.2       9.5   2000   7.9                                     23    50.4      10.1      13.8  5000   22.3                                    24    37.6      47.7      10.5  6000   24.3                                    25    40.8      48.6      7.8   8000   22.1                                    26    47.2      35.9      3.1   10000  24.8                                    27    47.7 (120)                                                                               13.2      25.7  3700   25.9                                    28    44.1      4.2       20.4  >10000 7.3                                     29    44.7 (130)                                                                               2.7       11.1  10000  15.3                                    30    64.7 (45) 13.4      8.7   1500   44.8                                    31    35.4      9.5       18.2  1500   23.5                                    32    47.7      26.2      12.4  2000   25.0                                    33    43.9      15.5      20.5  3000   28.3                                    34    43.1      12.1      16.4  5000   24.5                                    35    48.5      17.8      11.3  >10000 2.65                                    36    34.8      13.7      15.1  >10000 28.1                                    37    39.6      9.8       17.4  1000   5.3                                     38    37.5 (170)                                                                               18.0      20.9  1000   8.3                                     39    35.9      23.1      2.6   >10000 15.9                                    40    58.1 (120)                                                                               20.3      11.9  2000   30.3                                    41    47.4      14.6      14.4  3000   28.5                                    42    35.8      26.8      4.4   3000   10.7                                    43    34.0      0         3.5   >10000 86                                      44    57.7 (70) 15.6      10.5  2000   35.6                                    45    37.8 (>400)                                                                              12.5      17.7  5000   30.8                                    46    43.4 (400)                                                                               13.4      16.5  2000   34.5                                    47    20.9      13.1      18.3         15.6                                    48    26.0      12.5      20.5         18.3                                    49    10.7      18.2      28.5  8000   13.4                                    50    25.5      16.4      8.7   >10000 28.3                                    51    24.6      18.3      9.5          13.5                                    52    25.5      12.5      6.8          10.1                                    53    20.3      14.2      10.1         19.2                                    54    25.5      11.3      15.4         20.3                                    55    29.0      15.8      23.3         16.4                                    56    14.9      20.5      20.3  10000  15.1                                    57    16.1      10.3      12.5         6.5                                     58    15.3      19.8      20.1         14.6                                    59    20.7      22.8      25.6         14.1                                    60    13.2      6.3       4.0          12.3                                    61    16.7      15.1      15.8         8.5                                     62    12.5      10.2      12.3         7.8                                     63    11.8      8.2       15.6         6.2                                     64    21.4      6.6       28.5  3000   15.9                                    65    17.3      10.9      21.0         19.2                                    66    34.4      15.7      20.7  2000   20.5                                    67    20.0      19.1      18.5  2000   17.3                                    68    17.6      5.8       16.5         20.3                                    69    12.0      6.7       13.5         12.7                                    70    23.2      7.0       17.2         10.0                                    71    20.0      9.2       19.5         11.4                                    72    29.9      23.4      28.7  1000   30.2                                    73    32.1      10.0      20.3  6000   28.8                                    74    30.2      24.2      18.5  5000   28.9                                    75    29.5      22.0      30.7  5000   29.2                                    76    15.7      13.9      16.2  2500   18.4                                    77    13.2      10.8      25.1         17.5                                    78    12.5      5.4       19.9         20.2                                    79    33.2      20.8      26.8  1000   31.5                                    80    31.9      16.2      30.3         28.5                                    81    15.3      17.6      18.3         20.3                                    82    23.8      13.5      20.5         30.1                                    83    20.0      12.1      27.6         19.3                                    84    28.4      15.3      8.6   10000  16.0                                    85    18.7      10.2      18.7         16.2                                    86    17.7      8.3       28.3         35.6                                    87    18.7      11.2      30.1         25.8                                    88    21.6      5.6       24.5         29.3                                    89    27.6      4.3       22.6  10000  13.2                                    90    19.7      13.7      10.8         15.0                                    91    21.4      15.2      14.7         31.0                                    92    10.0      11.1      8.9          20.3                                    93    20.4      14.7      24.4         26.8                                    94    26.6      15.8      27.9  500    37.4                                    95    17.1      14.5      30.0         32.3                                    96    26.1      18.9      28.5         36.7                                    97    13.0      14.7      26.8         37.3                                    98    31.9      16.4      28.3  4000   35.4                                    99    34.1      15.5      29.5  5000   30.3                                    100   14.0      10.0      22.4         27.6                                    101   23.1      18.3      27.9         31.4                                    102   22.4      15.2      30.4         29.7                                    103   29.7      14.2      29.5  500    35.8                                    104   27.4      13.2      25.3  3000   30.5                                    105   33.6      14.1      24.1  4000   31.4                                    106   26.4      7.3       20.3  1000   20.2                                    107   20.3      13.2      20.3         19.6                                    108   10.5      3.1       28.4         34.7                                    109   12.7      2.6       13.7         20.3                                    110   17.0      10.5      20.5         18.6                                    111   20.6      11.3      10.3         17.3                                    112   14.1      6.7       11.8         15.5                                    113   38.7      14.5      25.8  4000   30.4                                    114   33.2      18.3      26.8  2000   31.1                                    115   14.5      11.8      25.4         27.5                                    ______________________________________                                    

                  Table 2'                                                         ______________________________________                                         Active                                                                         ingredient                Acute                                                No.         Anti-inf.     toxicity                                             ______________________________________                                         116         59.8          4000                                                 117         53.3          1500                                                 118         32.7          2000                                                 119         60.7          2000                                                 120         38.3          750                                                  121         64.5          3000                                                 122         39.3          2000                                                 123         38.3          1500                                                 124         23.5          3000                                                 125         18.1          1000                                                 126         27.7          1000                                                 127         58.8          5000                                                 128         33.6          4000                                                 129         38.6          >10000                                               130         37.8          2000                                                 131         33.6          2000                                                 132         14.9          2000                                                 133         38.3          2000                                                 134         35.1          3000                                                 135         37.2          1000                                                 136         13.2          2000                                                 137         16.7          2000                                                 138         12.5          2500                                                 139         11.7          1000                                                 140         14.9          1000                                                 141         13.8          2000                                                 142         38.9          1500                                                 143         45.4          1500                                                 144         50.0          1500                                                 145         60.2          2000                                                 146         23.1          1000                                                 147         20.4          1000                                                 148         36.3          2000                                                 149         42.2          500                                                  150         14.0          2000                                                 151         15.3          2500                                                 152         22.6          1500                                                 153         27.8          1500                                                 154         29.0          >10000                                               155         31.8          >10000                                               156         43.0          >10000                                               157         37.4          >10000                                               158         32.7          2000                                                 159         15.9          1000                                                 160         10.8          2500                                                 161         20.9          5000                                                 162         13.0          1500                                                 163         16.4          1500                                                 164         29.0          >10000                                               165         19.2          5000                                                 166         21.5          5000                                                 ______________________________________                                    

Chronic Inflammation (Adjuvant-Induced Arthritis)

The effects of 1 4-n-butyl benzophenone and 2 4-n-butyl-2'-fluorobenzophenone against adjuvant-induced arthritis were studied.

For the study, adult female rats of Sprague Drawley strain weighing approximately 200 g were used. All rats received 0.1 ml of a suspension of dry heat-killed tubercle bacilli (human strains, commercial product of Difco Co.) in liquid paraffin (5 mg/ml, w/v) by a single intradermal injection into the tail.

The treatment of the animals by the test compounds were started fourteen days after injection of the adjuvant when arthritis developed sufficiently accompanying edema and erythema in paws. Each compound was orally given to animals daily for ten days. Dosage levels employed were 50 an 100 mg/kg/day. Phenylbutazone was used as the reference drug.

Evaluations were made using the following parameters.

(1) Body weight gain

(2) Relative reduction in edema of the hind paws.

Results are summarized as follows:

                  Table 1                                                          ______________________________________                                         Body Weight Gain                                                                              No. of                                                                               0        6      10 days                                   Compounds    mg/kg   rats    average                                           ______________________________________                                         Positive Control                                                                            --      8       202.0  195.9                                                                               194.6                                 4-n-butyl benzopheone                                                                       100     6       229.2  217.5                                                                               218.2                                 4-n-butyl benzopheone                                                                       200     7       214.1  213.3                                                                               220.1                                 4-n-butyl-2'-fluoro-                                                           benzophenone  50     8       222.6  223.0                                                                               232.0                                 4-n-butyl-2'-fluoro-                                                           benzophenone 100     10      211.8  205.8                                                                               214.4                                 Phenylbutazone                                                                               50     7       215.6  207.7                                                                               214.3                                 ______________________________________                                    

                  Table 2                                                          ______________________________________                                         Relative Change of Established Swelling                                        in Hind Paws                                                                                     Relative Volume                                                                Ratio of Swelling                                                                            6      10 days                                                         No. of                                                 Compounds       mg/kg   rats    average                                        ______________________________________                                         Positive Control                                                                               --      8       1.43   1.42                                    4-n-butyl benzophenone                                                                         100     6       0.97   1.02                                    "               200     7       0.76   0.75                                    4-n-butyl-2'-fluoro-                                                            benzophenone    50     8       0.74   0.76                                    "               100     10      0.78   0.73                                    Phenylbutazone   50     7       0.75   0.75                                    ______________________________________                                    

No side effect considered to be related to the test compounds was seen during the study, while phenylbutazone caused the hemorrhage and the ulceration of stomach in most of the animals at dosage levels of 50 and 100 mg/kg/day. 

What is claimed is:
 1. A method for reducing chronic inflammation in a mammal, which comprises: administering to said mammal a therapeutically acceptable amount of 4-n-butyl-benzophenone. 